Processes for the preparation of 2-fluoro 6-11 bicyclic erythromycin derivatives

ABSTRACT

The present invention relates to processes and intermediates for the preparation of 2-fluoro 6-11 bicyclic erythromycin derivatives. In particular, the present invention relates to processes and intermediates for the preparation of a compound of formula (X-c):

RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.12/463,140, filed May 8, 2009, which claims the benefit of U.S.Provisional Application No. 61/051,857, filed on May 9, 2008, U.S.Provisional Application No. 61/051,862, filed on May 9, 2008, U.S.Provisional Application No. 61/076,208, filed on Jun. 27, 2008, U.S.Provisional Application No. 61/076,213, filed on Jun. 27, 2008 and U.S.Provisional Application No. 61/095,100, filed on Sep. 8, 2008. Theentire teachings of the above applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to processes and intermediates useful inthe preparation of 2-fluoro 6,11-bridged erythromycin derivatives.

BACKGROUND OF THE INVENTION

Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic family (14-, 15- and 16-membered ring derivatives) shows awide range of characteristics (antibacterial spectrum, side-effects andbioavailability). Among the commonly used macrolides are erythromycin,clarithromycin, and azithromycin. Macrolides possessing a 3-oxo moietyin place of the 3-cladinose sugar are known as ketolides and have shownenhanced activity towards gram-negative bacteria and macrolide resistantgram-positive bacteria. The search for macrolide compounds which areactive against MLS_(B)-resistant strains(MLS_(B)=Macrolides-Lincosamides-type B Streptogramines) has become amajor goal, together with retaining the overall profile of themacrolides in terms of stability, tolerance and pharmacokinetics.

SUMMARY OF THE INVENTION

The present invention provides methods for preparing bridged macrocycliccompounds. In one embodiment of the invention, an erythromycinderivative of formula I is reacted with a compound of formula II in thepresence of a palladium (0) catalyst. The invention further relates toincreasing product yield and decreasing process steps for intermediateand large scale production of bridged macrolides.

DETAILED DESCRIPTION OF THE INVENTION

The processes of the present invention are suitable for synthesizing2-fluoro 6-11 bicyclic erythromycin and ketolide derivatives, orpharmaceutically acceptable salts thereof.

In one embodiment, the invention provides for a process of preparing acompound of formula (XI):

the process comprising the steps of:

-   -   (a) halogenating (5-bromo-pyridin-2-yl)-methanol with a        chlorinating reagent to form a compound of formulae (XI-a),        infra;    -   (b) treating compound (XI-a) with

-   -    wherein A and B are each independently hydrogen, a substituted        or unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group; or A and B taken together with the carbon to        which they are attached form a cyclic moiety selected from:        aryl, substituted aryl, heterocyclic, substituted heterocyclic,        alicyclic, or substituted alicyclic, in the presence of a base        to yield compounds of formulae (XI-b), infra;    -   (c) treating compound (XI-b) with a tin reagent in the presence        of a metallic catalyst to provide compounds of formula (XI-c),        infra;    -   (d) reacting compound (XI-c) with

-   -    wherein C and D are each independently hydrogen, a substituted        or unsubstituted aliphatic group, a substituted or unsubstituted        cyclic group, a substituted or unsubstituted heterocyclic group,        a substituted or unsubstituted aryl group, a substituted or        unsubstituted alicyclic group, or a substituted or unsubstituted        heteroaryl group; or A and B taken together with the carbon to        which they are attached form a cyclic moiety selected from:        aryl, substituted aryl, heterocyclic, substituted heterocyclic,        alicyclic, or substituted alicyclic and wherein X is a leaving        group, in the presence of a metallic catalyst to provide        compounds of formula (XI-d):

-   -    and    -   (e) hydrolyzing the compound of formula (XI-d) with a base in a        protogenic organic solvent or aqueous solution.

Preferably, for step a, the chlorinating agent is thionyl chloride;and/or for step b, the base is N,N-diisopropylethylamine; and/or forstep c, the tin reagent is hexamethylditin, the metallic catalyst istetrakis(triphenylphosphine)palladium(0); and/or for step d, themetallic catalyst is tetrakis(triphenylphosphine)palladium(0); and/orfor step e, the base is methylamine.

In another embodiment, the invention provides for a process of preparinga compound of formula (XI):

the process comprising the steps of:

-   -   (a) treating (5-bromo-pyridin-2-yl)-methanol with a tin reagent        in the presence of a metallic catalyst to provide compounds of        formula (XI-f), infra;    -   (b) reacting compound (XI-f) with

-   -    wherein C and D are as previously defined and X is a leaving        group in the presence of a metallic catalyst to provide        compounds of formula (XI-g), infra;    -   (c) treating compound (XI-g) with compounds of formula

-   -    wherein A and B are as previously defined, in the presence of        dehydrating agents (a type of Mitsunobu reaction) to yield        compounds of formulae (XI-d):

-   -    and    -   (d) hydrolyzing the compound of formula (XI-d) with a base in a        protogenic organic solvent or aqueous solution.

Preferably, for step a, the tin reagent is hexamethylditin and/or themetallic catalyst is tetrakis(triphenylphosphine)palladium(0); and/orfor step b, the metallic catalyst istetrakis(triphenylphosphine)palladium(0); and/or for step c, thedehydrating agents (a type of Mitsunobu reaction) are triphenylphosphinetogether with DIAD; and/or for step d, the base is methylamine.

The invention further provides processes which are suitable forsynthesizing 2-fluoro 6-11-bicyclic erythromycin and ketolidederivatives, or pharmaceutically acceptable salts thereof. In oneembodiment, the process comprises the step of reacting a compound offormula (I):

or a pharmaceutically acceptable salt thereof with a compound of formulaII:

to produce a compound of formula III:

optionally in the presence of a palladium catalyst,

wherein,

Each R₁ is independently selected from hydrogen, acyl, silane, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, saturated or unsaturatedheterocyclic group;

Each of R₃ and R₄ is independently selected from hydrogen, acyl, asubstituted or unsubstituted, saturated or unsaturated aliphatic group,a substituted or unsubstituted, saturated or unsaturated alicyclicgroup, a substituted or unsubstituted aromatic group, a substituted orunsubstituted heteroaromatic group, saturated or unsaturatedheterocyclic group; or can be taken together with the nitrogen atom towhich they are attached to form a substituted or unsubstitutedheterocyclic or heteroaromatic ring;

Q is independently selected from R₁, OR₁, or OC(O)R₁;

Z is selected from R₁, OR₁, OC(O)R₁, OC(O)NR₃R₄, OS(O)_(n)R₁, or

one of J or G is hydrogen and the other is selected from R₁, OR₁, orNR₃R₄;

or, J and G, taken together with the carbon atom to which they areattached, are selected from C═O, C═NR₁, C═NOR₁, C═NO(CH₂)_(m)R₁,C═NNHR₁, C═NNHCOR₁, C═NNHCONR₃R₄, C═NNHS(O)_(n)R₁, or C═N—N═CHR₁;

R₁₁ is independently selected from R₁;

R_(p) is independently selected from R₁;

m is an integer, preferably from 0 to 8; and

n is 0, 1, or 2.

Preferred embodiments of the compound of Formula I are the compounds ofFormulas I-a and I-b:

In a most preferred embodiment, the compound of Formula I is a compoundof formula (I-c):

Although compounds of formula I are preferred, other macrocycliccompounds which contain two or more nucleophilic moieties (e.g. —OH,—NH₂, —NH—, etc.) may be substituted for the starting material offormula I.

Preferred embodiments of the compound of formula II are compoundswherein R₁₁ is hydrogen and/or R₁ is tert-butyl.

Compounds of formula (II) that are useful in the preparation ofcompounds of formula (III), are prepared by the process comprising thestep of reacting a compound of formula (II-a):

with a C₁-C₆ alkyl anhydride in the presence of a phase transfercatalyst.

Preferred embodiments of compounds of Formula III include the compoundsof Formulas III-a and III-b:

A most preferred embodiment of the compound of Formula III is thecompound of Formula III-c:

Compounds of formula (III) are useful as intermediates in thepreparation of compounds of formula (IV):

Preferred embodiments of the compound of formula IV are compounds offormulas (IV-a) and (IV-b):

A most preferred embodiment of the compounds of formula (IV) is acompound of formula (IV-c):

Another embodiment of the present invention, therefore, is a processcomprising the step of hydrolyzing a compound of formula (III) withaqueous acid to provide a compound of formula (IV).

Compounds of formula (IV) are useful as intermediates in preparingcompounds of formula (V):

Preferred embodiments of the compounds of formula (V) are compounds offormulas (V-a) and (V-b):

Yet a further embodiment of the present invention, therefore, is aprocess comprising the step of reducing a compound of formula (IV) witha reducing agent to provide a compound of formula (V).

Compounds of formula (V) are useful as intermediates in the preparationof compounds of formula (VI):

Preferred embodiments of the compounds of formula (VI) are compounds offormula (VI-a) and (VI-b):

Yet another embodiment of the present invention, therefore, is a processcomprising the step of acylating a compound of formula (V) with anacylating agent to provide a compound of formula (VI).

Compounds of formula (VI) are useful as intermediates in the preparationof compounds of formula (VII):

Preferred embodiments of the compounds of formula (VII) are compounds offormulas (VII-a) and (VII-b):

Yet another embodiment of the present invention, therefore, is a processwhich comprises the step of oxidizing a compound of formula (VI) with anoxidizing agent or agents to provide a compound of formula (VII).

Compounds of formula (VII) are useful as intermediates in thepreparation of compounds of formula (VIII):

Preferred embodiments of the compound of formula (VIII) are compounds offormulas (VIII-a), (VIII-b) and (VIII-c):

Yet another embodiment of the present invention, therefore, is a processwhich comprises the step of fluorinating a compound of formula (VII)with a fluorinating agent or agents in the presence of a base to providea compound of formula (VIII).

Compounds of formula (VIII) are useful as intermediates in thepreparation of compounds of formula (IX):

Preferred embodiments of the compounds of formula (VIII) are compoundsof formulas (IX-a) and (IX-b):

Yet a further embodiment of the present invention, therefore, is aprocess comprising the step of oxidatively cleaving a compound offormula (VIII) with a cleaving reagent or reagents which are capable ofperforming oxidative cleavage to provide a compound of formula (IX).

Compounds of formula (IX) are useful as intermediates in the synthesisof compounds of formula (X):

Preferred embodiments of the compounds of formula (X) are compounds offormulas (X-a) and (X-b):

A most preferred embodiment of the compound of formula (X) is a compoundof formula (X-c):

A further embodiment of the present invention, therefore, is a processas described above in combination with the step of reacting a compoundof formula (IX) with a compound of formula (XI): R₁—O—NH₂(XI) to providea compound of formula (X). In a preferred embodiment of this process, acompound of formula (IX) is treated with a compound of formula (XI):

to provide a compound of formula (X-c).

A compound of formula (XI) is a particularly useful intermediate in theprocess of the present invention and can be prepared by the processcomprising the steps of:

-   (a) halogenating (5-bromo-pyridin-2-yl)-methanol with a chlorinating    reagent to form a compound of formulae (XI-a):

-   (b) treating compound (XI-a) with

-    in the presence of base to yield compounds of formulae (XI-b):

-   wherein A and B are each independently hydrogen, a substituted or    unsubstituted aliphatic group, a substituted or unsubstituted cyclic    group, a substituted or unsubstituted heterocyclic group, a    substituted or unsubstituted aryl group, a substituted or    unsubstituted alicyclic group, or a substituted or unsubstituted    heteroaryl group; or A and B taken together with the carbon to which    they are attached form a cyclic moiety selected from: aryl,    substituted aryl, heterocyclic, substituted heterocyclic, alicyclic,    or substituted alicyclic;-   (c) treating compound (XI-b) with a tin reagent in the presence of a    metallic catalyst to provide compounds of formula (XI-c):

where Y is an aliphatic group;

-   (d) reacting compound (XI-c) with

-    wherein X is a leaving group in the presence of a metallic catalyst    to provide compounds of formula (XI-d):

-   wherein C and D are each independently hydrogen, a substituted or    unsubstituted aliphatic group, a substituted or unsubstituted cyclic    group, a substituted or unsubstituted heterocyclic group, a    substituted or unsubstituted aryl group, a substituted or    unsubstituted alicyclic group, or a substituted or unsubstituted    heteroaryl group; or A and B taken together with the carbon to which    they are attached form a cyclic moiety selected from: aryl,    substituted aryl, heterocyclic, substituted heterocyclic, alicyclic,    or substituted alicyclic;-   (e) hydrolyzing the compound of formula (XI-d) with a base in a    protogenic organic solvent or aqueous solution.

In yet another embodiment of the invention a compound of formula (XI)can be prepared by the process comprising the steps of:

-   (a) treating (5-bromo-pyridin-2-yl)-methanol with a tin reagent in    the presence of a metallic catalyst to provide compounds of formula    (XI-f):

where Y is an aliphatic group;

-   (b) reacting compound (XI-f) with

-    wherein C and D are as previously defined and X is a leaving group    in the presence of a metallic catalyst to provide compounds of    formula (XI-g):

-   (c) treating compound (XI-g) with compounds of formula

-    wherein A and B are as previously defined in the presence of    dehydrating agents (a type of Mitsunobu reaction) to yield compounds    of formulae (XI-d):

-   (d) hydrolyzing the compound of formula (XI-d) with a base in a    protogenic organic solvent or aqueous solution.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” is non-aromatic moiety that may contain anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic and preferably contains betweenabout 1 and about 24 carbon atoms, more typically between about 1 andabout 12 carbon atoms. In addition to aliphatic hydrocarbon groups,aliphatic groups include, for example, polyalkoxyalkyls, such aspolyalkylene glycols, polyamines, and polyimines, for example. Suchaliphatic groups may be further substituted.

Suitable aliphatic or aromatic substituents include, but are not limitedto, —F, —Cl, —Br, —I, —OH, protected hydroxy, aliphatic ethers, aromaticethers, oxo, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen (such as perhaloalkyls), C₂-C₁₂-alkenyl optionally substitutedwith halogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH -C₁-C₁₂-alkyl, —NH -C₂-C₁₂-alkenyl, —NH-C₂-C₁₂-alkenyl, —NH -C₃-C₁₂-cycloalkyl, —NH -aryl, —NH -heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —CO₂—C₁-C₁₂-alkyl,—CO₂—C₂-C₁₂-alkenyl, —CO₂—C₂-C₁₂-alkynyl, —CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, —CO₂-heteroaryl, —CO₂-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂—-heteroaryl, —NHCO₂—-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH-C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, alkadienes and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₁₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byone, two, three or more aliphatic substituents.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The terms “aryl” or “aromatic” as used herein, refer to a mono- orbicyclic carbocyclic ring system having one or two aromatic ringsincluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, indenyl and the like.

The terms “substituted aryl” or “substituted aromatic,” as used herein,refer to an aryl or aromatic group substituted by one, two, three ormore aromatic substituents.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkyl residue.Examples include, but are not limited to, benzyl, phenethyl and thelike.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by one, two, three or morearomatic substituents.

The terms “heteroaryl” or “heteroaromatic,” as used herein, refer to amono-, bi-, or tri-cyclic aromatic radical or ring having from five toten ring atoms of which at least one ring atom is selected from S, O andN; zero, one or two ring atoms are additional heteroatoms independentlyselected from S, O and N; and the remaining ring atoms are carbon,wherein any N or S contained within the ring may be optionally oxidized.Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike. The heteroaromatic ring may be bonded to the chemical structurethrough a carbon or hetero atom.

The terms “substituted heteroaryl” or “substituted heteroaromatic,” asused herein, refer to a heteroaryl or heteroaromatic group, substitutedby one, two, three, or more aromatic substituents.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl.

The term “substituted alicyclic,” as used herein, refers to an alicyclicgroup substituted by one, two, three or more aliphatic substituents.

The term “heterocyclic,” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (v) any ofthe above rings may be fused to a benzene ring, and (vi) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl.

The term “substituted heterocyclic,” as used herein, refers to aheterocyclic group, as previously defined, substituted by one, two,three or more aliphatic substituents.

The term “heteroarylalkyl,” as used herein, to an heteroaryl groupattached to the parent compound via a C₁-C₃ alkyl or C₁-C₆ alkylresidue. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one, two, or three or more aromatic substituents.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl).

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl), —C(O)NH₂,NHC(O)(C₁-C₁₂ alkyl), N(C₁-C₁₂ alkyl)C(O)(C₁-C₁₂ alkyl) and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “leaving group”, as used herein, means a functional group oratom which can be displaced by another functional group or atom in asubstitution reaction, such as a nucleophilic substitution reaction. Byway of example, representative leaving groups include chloro, bromo andiodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

The term “oxidizing agent(s),” as used herein, refers to reagents usefulfor oxidizing the 3-hydroxyl of the macrolide ring to the 3-carbonyl.Oxidizing agents suitable in the present process are either Swernoxidation reagents (dimethyl sulfoxide and an electrophilic compoundselected from dicyclohexylcarbodiimide, acetic anhydride,trifluoroacetic anhydride, oxalyl chloride, or sulfur trioxide), DessMartin oxidation reagents, or Corey-Kim oxidation reagents. A preferredmethod of oxidation is the use of the Corey-Kim oxidation reagentsN-chlorosuccinimide-dimethyl sulfide complex.

The term “palladium catalyst,” as used herein, refers to optionallysupported palladium(0) such as palladium metal, palladium on carbon,palladium on acidic, basic, or neutral alumina, and the like;palladium(0) complexes such as tetrakis(triphenylphosphine)palladium(0)tris(dibenzylideneacetone)dipalladium(0); palladium(II) salts such aspalladium acetate or palladium chloride; and palladium(II) complexessuch as allylpalladium(II) chloride dimer,(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II),bis(acetato)bis(triphenylphosphine)palladium(II), andbis(acetonitrile)dichloropalladium(II).

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995).

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans- isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of Formula I. Various forms of prodrugs are known in the art,for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the formula I. Forexample, compounds of formula I having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of formula I. The amino acid residuesinclude but are not limited to the 20 naturally occurring amino acidscommonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Suitable concentrations of reactants is 0.01M to 10M, typically 0.1M to1M. Suitable temperatures include -10° C. to 250° C., typically -78° C.to 150° C., more typically -78° C. to 100° C., still more typically 0°C. to 100° C. Reaction vessels are preferably made of any material whichdoes not substantial interfere with the reaction. Examples includeglass, plastic, and metal. The pressure of the reaction canadvantageously be operated at atmospheric pressure. The atmospheresincludes, for example, air, for oxygen and water insensitive reactions,or nitrogen or argon, for oxygen or water sensitive reactions.

The term “in situ,” as used herein, refers to use of an intermediate inthe solvent or solvents in which the intermediate was prepared withoutremoval of the solvent.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

ABBREVIATIONS

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

Ac for acetyl;

AIBN for azobisisobutyronitrile;

Bu₃SnH for tributyltin hydride;

CDI for carbonyldiimidazole;

dba for dibenzylidene acetone;

dppb for diphenylphosphino butane or 1,4-bis(diphenylphosphino)butane;

DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;

DEAD for diethylazodicarboxylate;

DMAP for dimethylaminopyridine;

DMF for dimethyl formamide;

DPPA for diphenylphosphoryl azide;

EtOAc for ethyl acetate;

HPLC for high-pressure liquid chromatography;

MeOH for methanol;

NaN(TMS)₂ for sodium bis(trimethylsilyl)amide;

NMMO for N-methylmorpholine N-oxide;

TEA for triethylamine;

THF for tetrahydrofuran;

TPP or PPh₃ for triphenylphosphine;

MOM for methoxymethyl;

Boc for t-butoxycarbonyl;

Bz for benzyl;

Ph for phenyl;

POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II);

TBS for tert-butyl dimethylsilyl; or

TMS for trimethylsilyl.

All other abbreviations used herein, which are not specificallydelineated above, shall be accorded the meaning which one of ordinaryskill in the art would attach.

SYNTHETIC SCHEMES

The present invention will be better understood in connection withSchemes 1-6. It will be readily apparent to one of ordinary skill in theart that the process of the present invention can be practiced bysubstitution of the appropriate reactants and that the order of thesteps themselves can be varied.

Erythromycins can be protected as 9-oximes of formula (I-a) as describedin U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,386; and 4,670,549.Reaction of erythromycin A with hydroxylamine and formic acid inmethanol provides a compound of formula (I) wherein Q is OH and Z is

which can be further derivatized without isolation. The preferred amountof hydroxylamine is about 7 to about 10 molar equivalents per molarequivalent of erythromycin A. From about 2 to about 5 molar equivalentsof formic acid are used for each molar equivalent of erythromycin A.

The 2′- and 4″-hydroxyl groups as well as the hydroxyl of the 9-oxime ofcompounds of formula (I-a) can be protected sequentially orsimultaneously by reaction with a suitable hydroxyl-protecting reagentin an aprotic solvent, optionally in the presence of catalytic amountsof base, such as DMAP and/or TEA, as described in U.S. Pat. No.5,892,008, to provide a compound of formula (I-b). Typicalhydroxyl-protecting reagents include acetylating agents and silylatingagents such as acetyl chloride, acetic anhydride, benzoyl chloride,benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, andtrialkylsilyl chlorides. A preferred hydroxyl-protecting reagent of thepresent invention is acetic anhydride.

Compounds of formula II, useful in the preparation of compounds offormula III, are prepared by treating 2-methylene-1,3-propanediol withdi-tert-butyl dicarbonate in an aprotic solvent, in the presence of aphase transfer catalyst (PTC) and an aqueous base. PTCs suitable for thepresent process include, but are not limited to, tetrabutylammoniumbromide, tetrabutylammonium bromide, tetrabutylammonium chloride,tetrabutylammonium fluoride trihydrate, tetrabutylammonium hydrogensulfate, tetrabutylammonium iodide, tetrabutylammonium thiocyanate,tetrabutylammonium tetrafluoroborate, benzyltetrabutylammonium chloride,and the like; the preferred of which is tetrabutylammonium hydrogensulfate. In a preferred embodiment of the present conversion, theaprotic solvent is dichloromethane, the aqueous base is 4M to 8M NaOH.

As illustrated in Scheme 1, step A, erythromycin derivatives of formula(I-b) are converted in the present invention to compounds of formula(III-a) by the treatment of the former with compounds of formula (II):

preferably where R₁ is tert-butyl, isopropyl, or isobutyl and R₁₁ ishydrogen. In a preferred embodiment, the conversion takes place in anaprotic solvent, at a temperature range of between 30° C. and 100° C.,in the presence of a palladium catalyst and an additive for a period ofless than about 12 hours.

Alkylation of a compound of formula (I-b) with a compound of formula(II) preferably takes place in the presence of a palladium catalyst.Most palladium (0) catalysts are expected be effective in this process.Some palladium (II) catalysts, such as palladium (II) acetate, which areconverted into a palladium (0) species in-situ by a phosphine, will beeffective as well. See, for example, Beller et al. Angew. Chem. Int. Ed.Engl., 1995, 34 (17), 1848. A suitable palladium catalyst for thisreaction includes, but is not limited to, palladium (II) acetate,tetrakis(triphenylphospine)palladium (0),tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃),tetradi(benzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process. A preferred palladium catalyst forthis process is a palladium(0) catalyst. A particularly preferredpalladium catalyst for this process is Pd₂(dba)₃.

In addition, the process is preferably performed in the presence of anadditive. Examples of preferred additives include monodentatephosphorus-containing ligands of formulas P(R_(C))₃ (phosphines) andP(OR_(D))₃ (phosphites), wherein each R_(C) is independently hydrogen;alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such ascyclopropyl and cyclohexyl; optionally substituted aryl, such as phenyl,naphthyl, and ortho-tolyl; and optionally substituted heteroaryl such asfuryl and pyridyl; and wherein each R_(D) is independently alkyl such asmethyl, ethyl, and tert-butyl; cycloalkyl, such as cyclopropyl andcyclohexyl; optionally substituted aryl, such as phenyl, naphthyl, andortho-tolyl; and optionally substituted heteroaryl, such as furyl andpyridyl. Specific examples of additives include, but are not limited to,tri(alkyl)phosphines such as trimethylphosphine, triethylphosphine,tributylphosphine, and the like; tri(cycloalkryl)phosphines such astricyclopropylphosphine, tricyclohexylphosphine, and the like;tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine,and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine,tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such astrimethylphosphite, triethylphosphite, tributylphosphite, and the like;tri(cycloalkyl)-phosphites such as tricyelopropylphosphite,tricyclohexylphosphite, and the like; tri(aryl)phosphites such astriphenylphosphite, trinaphthylphosphite, and the like; andtri(heteroaryl)phosphites such as tri(fury-2-yl)phosphite,tri(pyrid-3-yl)phosphite, and the like. The term “additive,” as usedherein, also refers to bidentate phosphines such as1,4-bis(diphenylphosphino)butane (dppb),1,2-bis(diphenyl-phosphino)ethane (dppe),1,1-bis(diphenylphosphino)methane (dppm),1,2-bis(dimethyl-phosphino)ethane (dmpe),1,1′-bis(diphenylphosphino)ferrocene (dppf), and the like. Aparticularly preferred additive of the instant process is1,4-bis(diphenylphosphino)butane (dppb).

The process is carried out in an aprotic solvent. Suitable aproticsolvents include, but are not limited to, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone,hexamethylphosphoric triamide, 1,2-dimethoxyethane, methyl-tert-butylether, heptane, acetonitrile, isopropyl acetate and ethyl acetate.Preferred aprotic solvents are tetrahydrofuran or toluene.

The instant conversion is performed preferably at an elevatedtemperature between 30 and 100° C. A particularly preferred temperaturerange is between 55° C. and 85° C. A most preferred temperature rangefor the instant alkylation process is between 60° C. and 75° C.

The instant alkylation process is generally conducted until at least 50%completion, preferably at least about 70% completion, typically until atleast 95% completion. Generally, the reaction time will be less thanabout 12 hours. A preferred reaction time range for the presentalkylation process is less than about 8 hours. A most preferred reactiontime range for the present alkylation process is less than about 7hours.

A compound of formula (III-a), wherein R₆ and R_(p) are as previouslydefined, are converted to a compound of formula (IV-b), wherein R_(p) isas previously defined, via the process illustrated in Scheme 1, step B.The removal of the cladinose moiety may be achieved either by mild acidhydrolysis or by enzymatic hydrolysis, at a temperature range of between−10° C. and 80° C., for a time period of from 0.5 to 24 hours, to afforda compound of formula (IV-b). Representative acids include dilutehydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid,dichloroacetic acid or trifluoroacetic acid. Suitable solvents for thereaction include water, methanol, ethanol, isopropanol, butanol and thelike. In a preferred embodiment, the removal of the cladinose moiety isachieved by treatment with aqueous hydrochloric acid, for a period of 1to 2 hours, at a temperature between 50° C. and 70° C. In a mostpreferred embodiment, 1M aqueous hydrochloric acid is used at atemperature of about 60° C.

As illustrated in Scheme 2, Step A, conversion of a compound of formula(IV-a) to a compound of formula (V), may be achieved by treating theformer with a reducing agent. Reducing agents suitable for thisconversion include, but are not limited to, lithium aluminum hydride,titanium(III)chloride, borane, and various sulfides such as sodiumhydrogen sulfide and sodium nitrite. For a more detailed account ofoxime reduction reaction, see J. March in “Advanced Organic Chemistry”4^(th) ed., Wiley & Son, Inc, 1992. In a particularly preferredembodiment, a compound of formula (IV-a) is treated with a titanium(III)reducing agent (preferably titanium(III)chloride), under acidicconditions, typically in a protogenic organic solvent. Preferred acidsinclude, but are not limited to, acetic acid, formic acid, dilutehydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and thelike. A particularly preferred acid for the present conversion isaqueous hydrochloric acid. Protogenic organic solvents suitable in thispreferred embodiment include, but are not limited to, mixtures of waterand methanol, ethanol, isopropanol, or butanol. A particularly preferredprotogenic organic solvent for the present conversion is ethanol. Theconversion is carried out between 10° C. and 110° C. (preferably betweenabout 20° C. and 50° C.) and over a period of less than about 10 hours(preferably between 2 to 4 hours).

As illustrated in Scheme 2, Step B, compounds of formula (V-a) can beconverted to compounds of formula (VI) by treating the former with anacylating agent.

In a preferred embodiment, the conversion is carried out in an aproticsolvent. Acylating agents suitable for the instant conversion include,but are not limited to, acetyl chloride, acetic anhydride, propionicanhydride, benzoyl chloride, benzoic anhydride, and benzylchloroformate.

Aprotic solvents suitable for the present conversion aredichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidinone,dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide, a mixture thereof or a mixture of one ofthese solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane,1,2-dichloroethane, acetonitrile, ethyl acetate, acetone, and the like.A preferred aprotic solvent of the present process is selected fromdichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran,N-methylpyrrolidinone or mixtures thereof. A particularly preferredaprotic solvent is dichloromethane.

Scheme 3 illustrates the process converting a compound of formula (VI)into a compound of formula (VII) by oxidation of the 3-position alcoholusing an oxidizing agent or agents. Oxidizing agents suitable in thepresent process are either Swern oxidation reagents (dimethyl sulfoxideand an electrophilic compound selected from dicyclohexylcarbodiimide,acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, or sulfurtrioxide), Dess-Martin periodane, or Corey-Kim oxidation reagents. Apreferred method of oxidation is the use of the Corey-Kim oxidationreagents N-chlorosuccinimide and dimethyl sulfide. The reactiontypically takes place in an aprotic solvent at a temperature of betweenabout −78° to 25° C. The reaction time typically is less than 12 hours.A more thorough discussion of the state of the art regarding oxidationof secondary alcohols can be found in J. March in “Advanced OrganicChemistry” 4^(th) ed., Wiley & Son, Inc, 1992.

As illustrated in Scheme 3, conversion of a compound of formula (VII) toa compound of formula (VIII) may be achieved by treating the former witha fluorinating agent in the presence of a base. Suitable bases include,but are not limited to, lithium tert-butoxide, potassium tert-butoxide,and sodium hydride. A particularly preferred base is lithiumtert-butoxide. Suitable fluorinating agents include, but are not limitedto, N-fluorobenzenesulfonimide (NFSI), Selectfluor®, anddiethylaminosulfur trifluoride (DAST). A particularly preferredfluorinating agent is NFSI. Organic solvents suitable in this preferredembodiment include, but are not limited to, tetrahydrofuran,N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, tert-butanol, or amixture thereof. A particularly preferred solvent is a mixture oftert-butanol and NMP. The reaction typically takes place at atemperature of between about −78° to 25° C. The reaction time typicallyis less than 12 hours. A more thorough discussion of the state of theart regarding fluorination of ketones can be found in J. March in“Advanced Organic Chemistry” 5^(th) ed., Wiley & Son, Inc, 2001.

A compound of formula (IX) may be prepared by treating a compound offormula (VIII) with a reagent or reagents capable of performingoxidative cleavage. Oxidative cleavage may be performed by, for example,ozonolysis or by treatment with an oxidant followed by a cleavingreagent. Ozonolysis may be achieved by treating the alkene of a compoundof formula (VIII) with ozone followed by decomposition of the ozonidewith the appropriate reducing agent. Suitable reducing agents for thisprocess include, but are not limited to, dimethyl sulfide, zinc,trivalent phosphorous compounds, sodium sulfite, and the like. Thereaction is typically carried out in an inert solvent such as, but notlimited to, methanol, ethanol, ethyl acetate, glacial acetic acid,chloroform, methylene chloride or hexanes or mixtures thereof,preferably methanol, preferably at about −78° to −20° C. Preferredreducing agents include, but are not limited to, triphenylphosphine,trimethyl phosphite, thiourea, and dimethyl sulfide, preferablytriphenylphosphine. A more thorough discussion of ozonolysis and theconditions there for can be found in J. March “Advanced OrganicChemistry” ^(4th) ed., a , Wiley & Son, Inc, 1992.

An alternative method for the preparation of a compound of formula (IX)involves dihydroxylation of a compound of formula (VIII) by an oxidantfollowed by treatment with a cleaving reagent. The glycol is firstprepared by reacting alkene with an oxidant. Suitable oxidants for thepresent process include, but are not limited to, permanganate ion andosmium tetroxide. The process may utilize stoichiometric amounts ofosmium tetroxide, or, if in the presence of an additional oxidant suchas hydrogen peroxide, tert-butyl hydroperoxide,N-methylmorpholine-N-oxide, or barium chlorate only catalytic amounts ofosmium tetroxide are necessary. Dihydroxylation reactions can be carriedout in a variety of solvents including: 1,4-dioxane, tetrahydrofuran,tert-butanol and diethyl ether, preferably at a temperature of between−15° C. and 15° C.

The resulting glycol can be cleaved by a variety of cleaving reagentsincluding, but not limited to, periodic acid, lead tetraacetate,manganesedioxide, potassium permanganate, sodium metaperiodate, andN-iodosuccinamide. Preferably the cleavage reagent is sodium periodate,the solvent is preferably a mixture of acetone, THF, ethanol, methanolor 1,4-dioxane and water at a temperature of between 0° to 80° C.

A compound of formula (IX-a) represents a useful intermediate which canbe further functionalized in a variety of ways. Scheme 4 details aprocedure for the conversion of a compound of formula (IX-a) into anoxime compound of formula (X-c), by first treating with hydroxylamine offormula (XI) followed by 2′-deacetylation. Oxime formation can beaccomplished under either acidic or basic conditions in a variety ofsolvents. Representative acids include, but are not limited to,hydrochloric, camphorsulfonic acid, phosphoric, sulfuric,para-toluenesulfonic, and pyridinium p-toluene sulfonate. Likewise baseswhich are useful include, but are not limited to, triethylamine,pyridine, diisopropylethyl amine, 1,5-lutidine, imidazole, and the like.Appropriate solvents include, but are not limited to, methanol, ethanol,water, tetrahydrofuran, 1,2-dimethoxyethane, and ethyl acetate.Preferably the reaction is run in ethanol using hydrochloric acid as theacid catalyst. The reaction temperature is generally −40° C. to 50° C.and the duration of the reaction is less than 12 hours. The deprotectioncan be achieved by for example methanolysis.

As outlined in Scheme 5, Step A, a compound of formula (XI-a) isprepared by reacting 5-bromo-2-hydroxymethyl-pyridine with achlorinating reagent.

A compound of formula (XI-b) is prepared by adding a compound of formula(5-2), to a compound of formula (XI-a), as illustrated in Step B,wherein A and B are as previously defined. The present conversionpreferably takes place in an aprotic solvent in the presence of a base.

A compound of formula (XI-c) is prepared, as illustrated in Step C ofScheme 5, wherein Y is an aliphatic group as previously defined, byreacting compound (XI-b) with a tin reagent in the presence of acatalyst, such as palladium(0) salt or other metal derivatives inorganic solvent, preferably in an aprotic solvent. In a preferredembodiment of the reaction, the reaction temperature is between 75° C.and 200° C. and the duration of the reaction is 6 to 48 hours. In aparticularly preferred embodiment of the reaction, the tin reagent ishexamethylditin, the catalyst istetrakis(triphenylphosphine)palladium(0) and the aprotic solvent istoluene.

As illustrated in Step D, wherein A, B, C and D are as previouslydefined and X is a leaving group, a compound of formula (XI-d) isprepared by reacting compound (XI-c) with a compound of formula (5-3) inthe presence of a catalyst, such as palladium(0) salt or other metalderivatives in organic solvent, preferably in an aprotic solvent. In apreferred embodiment of the reaction, the reaction temperature isbetween 75° C. and 200° C. and the duration of the reaction is 6 to 48hours. In a particularly preferred embodiment of the reaction, thecatalyst is tetrakis(triphenylphosphine)palladium(0) and the aproticsolvent is toluene.

A compound of formula (XI) is prepared, as illustrated in Step E ofScheme 5, by hydrolyzing the compound of formula (XI-d) with a base in aprotogenic organic solvent or an aqueous mixture thereof. Preferably thebase is either hydrazine ammonia, or methylamine.

As outlined in Scheme 6, Step A, wherein Y is an aliphatic group aspreviously defined, a compound of formula (XI-f) is prepared by reacting5-bromo-2-hydroxymethyl-pyridine (6-1) with a tin reagent in thepresence of a catalyst, such as palladium(0) salt or other metalderivatives in organic solvent, preferably in an aprotic solvent. Thepresent conversion preferably takes place in the same conditions asdescribed in Scheme 5, Step C, with different starting material offormula (6-1).

As illustrated in Step B, wherein C and D are as previously defined andX is a leaving group, a compound of formula (XI-g) is prepared byreacting compound (XI-f) with a compound of formula (6-2) in thepresence of a catalyst, such as palladium(0) salt or other metalderivatives in organic solvent, preferably in an aprotic solvent. Thepresent conversion preferably takes place in the same conditions asdescribed in Scheme 5, Step D, with different starting material offormula (XI-f).

As illustrated in Step C, wherein A, B, C and D are as previouslydefined, a compound of formula (XI-d) is prepared by reacting compound(XI-g) with a compound of formula (6-3) in the presence of dehydratingagents (a type of Mitsunobu reaction) in organic solvent, preferably inan aprotic solvent. In a preferred embodiment of the reaction, thereaction temperature is between 0° C. and 80° C. and the duration of thereaction is 1 to 24 hours. In a particularly preferred embodiment of thereaction, the dehydrating agent is triphenylphosphine together withdiisopropyl azodicarboxylate and the aprotic solvent is tetrahydrofuran.

In another embodiment of Scheme 6, a compound of formula (XI-d) isprepared as illustrated in Step C, by reacting compound (XI-g) with achlorinating reagent and then adding a compound of formula (6-3) asillustrated in Scheme 5, Step B, wherein A, B, C and D are as previouslydefined. The present conversion preferably takes place in the sameconditions as described in Scheme 5, Step A and B, with differentstarting material of formula (XI-g).

A compound of formula (XI) may be prepared from a compound of formula(XI-d) as outlined in Scheme 5.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Preparation of O-Bis(Boc)-2-Methylene-1,3-Propanediol(Compound of Formula II, wherein R₁₁ is Hydrogen and R₁ is tert-butyl)

To a solution of di-tert-butyl dicarbonate (6.6 kg) in methylenechloride (15.0 L, 15 volumes) was added 2-methylene-1,3-propanediol(1.00 kg) and phase transfer catalyst tetrabutylammonium hydrogensulfate(0.641 kg). The resulting reaction mixture was then agitated vigorouslyat about 15° C. while adding over a 2 hr period, 6M aqueous sodiumhydroxide solution (13.2 L) and controlling the temperature between 25to 30° C. The resulting two-phase reaction mixture was subsequentlyagitated for a period of 2-3 hrs at 25° C.

The aqueous layer was discarded and additional phase transfer catalysttetrabutylammonium hydrogensulfate (0.064 kg, 10% of the initialamount), di-tert-butyl dicarbonate (0.66 kg, 10% of the initial amount),and methylene chloride (2.0 L, 2 volumes) was added to the remainingorganic reaction mixture. To the reaction mixture was also added 6Maqueous sodium hydroxide solution (1.32 L, 10% of the initial amount)over a period of about 0.5 to 1 hr, while controlling the temperaturebetween 25 to 30° C. The resulting two-phase reaction mixture was thenagitated at about 25° C. for additional 3 to 4 hr. Allowing more than 3hrs of agitation time is often required to complete the hydrolysis ofthe excess di-tert-butyl dicarbonate. The aqueous layer was discarded.The resulting organic phase was washed with water (3×8.0 L), dilutedwith EtOAc (6 L, 6 volumes), and distilled to an oil foam withquantitative yield.

¹H (500 MHz, CDCl₃) δ 5.15, 4.98, 4.79, 4.68, 4.68, 4.33, 4.31, 3.89,3.77, 3.67, 3.45, 3.35, 3.19, 2.88, 2.78, 2.74, 2.42, 2.17, 2.11, 2.06,1.95, 1.72, 1.66, 1.51, 1.48, 1.43, 1.34, 1.27, 1.19, 1.19, 1.18, 1.14,1.13, 1.11, 0.95, 0.85.

Example 2 Preparation of Erythromycin A 9-oxime 9,2′,4″-triacetate(Compound of Formula (I-c))

To a solution of erythromycin A oxime (1.0 kg) in EtOAc (4 L, 4 volumes)was added TEA (0.744 L) and DMAP (48.9 g). While agitating andmaintaining a temperature of less than 40° C., to the resulting reactionmixture was added acetic anhydride (0.441 L) over a period of 1-5 hrs.The reaction mixture was then agitated for an additional 1-5 hr periodat about 25° C. Additional TEA (0.0744 L, 10% of initial amount) wasthen added to the reaction mixture, and subsequently additional aceticanhydride (0.0441 L, 10% of initial amount) was added over the course of30 min while maintaining a temperature of less than 35° C. This mixturewas then further agitated for 1.5-2 hr at about 25° C.

After the reaction had gone to completion, the reaction mixture wasdiluted with EtOAc (6 volumes), quenched with aqueous NaHCO₃ solution3.0 L (3 volumes), and agitated for 5-10 min at about 25° C. The aqueousphase was then discarded. The remaining organic mixture was washed withaqueous NaHCO₃ solution (3.0 L, 3 volumes) and 15% aqueous brine (3.0 L,3 volumes), and concentrated in vacuo. The concentrated solution wasthen taken up in acetonitrile (4.0 L, 4 volumes) and concentrated invacuo two times until crystallization occurs. Upon formation ofcrystals, the slurry was agitated at 10° C. to 15° C. for at least 2 hrand the crystals were collected and dried under vacuum to afford whitecrystalline product with a typical yield of 70-80%.

¹H (500 MHz, CDCl₃) δ 5.15, 4.98, 4.79, 4.68, 4.68, 4.33, 4.31, 3.89,3.77, 3.67, 3.45, 3.35, 3.19, 2.88, 2.78, 2.74, 2.42, 2.17, 2.11, 2.06,1.95, 1.72, 1.66, 1.51, 1.48, 1.43, 1.34, 1.27, 1.19, 1.19, 1.18, 1.14,1.13, 1.11, 0.95, 0.85.

¹³C (125 MHz, CDCl₃) δ 178.7, 175.4, 170.4, 170.0, 168.3, 100.6, 96.3,83.4, 79.4, 79.0, 77.4, 74.9, 74.0, 72.6, 72.2, 70.1, 67.7, 63.6, 63.4,49.5, 45.0, 40.7, 39.2, 37.4, 35.7, 34.5, 31.5, 28.6, 26.8, 21.8, 21.7,21.5, 21.3, 21.1, 20.0, 18.7, 18.4, 16.7, 16.1, 14.9, 10.9, 9.2.

Example 3 Preparation of 6,11-O,O-Bridged Erythromycin A 9-Oxime9,2′,4″-triacetate (Compound of Formula (III-c))

To a solution of the title compound of Example 2 (1.00 kg) in anhydrousTHF (5.0 L, 5 volumes) was added a solution of the title compound ofExample 1 (0.62 kg) in anhydrous THF (2.0 L, 2 volumes) while agitating.The resulting reaction mixture was subsequently degassed twice byapplication under reduced pressure and placed under nitrogen. To thedegassed reaction mixture was added 1,4-bis(diphenylphosphino)butane(dppb) (19.5 g), and tris(dibenzylideneacetone)dipalladium(0)[Pd₂(dba)₃] (20.8 g), after which the resulting reaction mixture wasimmediately degassed twice as previously described.

The degassed reaction mixture was then heated, while being agitated, toreflux [typically, reflux begins at about 65° C.] over the period ofabout 1 to 2 hrs and then held at a temperature of 67° C. to 69° C.,while being agitated, for a period of 6 hr. After the 6 hr period, thereaction mixture was allowed to cool to about 25° C. over the period of2 to 3 hrs and the reaction mixture was analyzed for completion by HPLC.

Once it had been determined that the reaction had gone to completion,the reaction was then filtered through a short pad (about 2 inchesthick) of silica gel 0.25-0.5 kg to remove the palladium catalyst,phosphine ligand, and other polar impurities. The reaction vessel wasthen rinsed with reagent-grade THF (2.0 L, 2 volumes), agitate/wash for10 min, and filtered through the short pad of silica gel, combining withfiltrate from the reaction mixture. The combined filtrate was thenconcentrated in vacuo to afford the title compound in THF solution. Thefinal remaining volume of the THF solution of the title compound wasapproximately 2-3 L (2-3 volumes) and was used directly in the followingstep without isolation.

Example 4 Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Oxime (Compound of Formula (IV-c))

To the concentrated solution of the title compound of Example 3 wasadded 1M hydrochloric acid solution in water (8.0 L, 8 volumes). Theresulting reaction mixture was subsequently agitated and heated to 60°C. over a period of 1-2 hr and then held at said temperature for anadditional 2 hr.

After the reaction had gone to completion (determined by HPLC), thereaction mixture was cooled to about 25° C. over the period of about 3hrs. The aqueous reaction mixture was then washed with methyl tert-butylether (MTBE) (4.0 L×2, 4 volumes×2) while agitating at 25° C. for 10min, keeping the aqueous layer. To the aqueous reaction mixture was thenadded saturated aqueous K₂CO₃ solution (about 0.8 kg of solid potassiumcarbonate in water) at 20 to 30° C. over the period of 1 to 2 hrs untilthe mixture is pH 9.5.

The resulting aqueous reaction mixture was then extracted EtOAc (4.0L×2, 4 volumes×2) while agitating at 25° C. for 10 min, keeping theupper organic layer. The combined organic phase was then washed withwater (4.0 L, 4 volumes) and subsequently concentrated in vacuo to avolume of 2-2.5 L. To the concentrated solution was added acetonitrile(4.0 L, 4 volumes) and concentrated in vacuo again until about 2 to 2.5L (2 to 2.5 volumes) remained. Once again, to the concentrated solutionwas added acetonitrile (2.0 L, 2 volumes) and concentrate in vacuo untilless than 2 L (<2 volumes) remains. The concentrated solution wasremoved from reduced pressure and agitated at 45° C. untilcrystallization began. The resulting slurry was then cooled to atemperature of 0-5° C. over a period of 4-5 hr and held at saidtemperature for an additional 2 hrs prior to collecting, washing, anddrying the crystalline form of the title compound. The typical yield forthis two-step one pot process (Pd-catalyzed bridge formation and sugarcleavage) is 40-45%.

¹H (500 MHz, CDCl₃) δ 5.09, 4.98, 4.97, 4.78, 4.74, 4.43, 4.39, 4.07,3.90, 3.84, 3.74, 3.67, 3.50, 3.43, 2.82, 2.79, 2.73, 2.62, 2.43, 2.31,2.08, 2.03, 1.77, 1.59, 1.46, 1.38, 1.35, 1.32, 1.24, 1.23, 1.22, 1.22,0.97, 0.97, 0.89.

¹³C (125 MHz, CDCl₃) δ 175.3, 170.2, 166.5, 143.7, 119.2, 99.7, 82.3,79.5, 78.2, 78.1, 77.6, 77.3, 77.0, 76.1, 74.0, 71.7, 69.0, 65.6, 63.4,43.9, 40.9, 37.5, 36.0, 34.3, 31.2, 25.7, 23.4, 21.7, 21.4, 20.0, 19.6,17.11, 15.7, 14.8, 12.0, 7.9.

Example 5 Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Imine Acetamide 2′-Acetate (Compound of Formula (VI-b)) Step 5a.Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A 9-ImineAcetamide 2′-Acetate (Compound of Formula (V))

To an agitating solution of the title compound of Example 4 (1.00 kg) inethanol (2 L, 2 volumes) was added 20% titanium (III) chloride solutionin aqueous 3% hydrochloric acid (2.847 kg or 2.33 L) over the period ofabout 1 hr via an addition funnel, while adjusting the addition rate tocontrol maintain the temperature between 25 to 35° C. After adding allof the titanium(III) chloride solution, the reaction mixture was thenagitated for an additional 3 hrs at a temperature between 25° C. and 30°C. until the reaction was completed (by HPLC). To the reaction mixturewas then added pre-chilled purified water (15 L, 15 volumes).

To the resulting aqueous reaction mixture was added a solution of sodiumhydroxide (50%, w/w, 0.466 L) over a period of 0.5-1 hr, while adjustingthe addition rate to maintain a temperature between 25 to 35° C., untilthe reaction mixture had reached a pH of between 6 to 7. The reactionmixture was then treated with saturated aqueous potassium carbonatesolution (0.666 L) at 25 to 35° C. over a period of 1 to 2 hrs until theresulting reaction mixture was pH 9 to 10.

The basic aqueous reaction mixture was then extracted five times withmethylene chloride (5.0 L×5, 5 volumes×5) and the combined organicextract is concentrated in vacuo until about 5 L remain. To theconcentrated reaction mixture was then added additional methylenechloride (5.0 L) and removed in vacuo to azeotropically remove wateruntil about 5 L remain. The resulting methylene chloride solution wasdirectly used in the subsequent step without isolation.

Step 5b. Preparation of the 9-Imine Acetate (Compound of Formula (VI-b)

Acetic anhydride (0.30 kg) is added to the concentrated solution fromStep 5a and the resulting mixture was agitated at 25 to 30° C. for 1.5hrs. After the acetylation reaction had gone to completion as evidencedby HPLC, the reaction mixture was concentrated in vacuo untilapproximately 2 L remained in the vessel. The remaining solution wasthen diluted with EtOAc (4.0 L, 4 volumes) and concentrated in vacuountil about 3 L remain. An additional amount of EtOAc (4.0 L, 4 volumes)was added to the concentrate and the diluted solution was concentratedonce again in vacuo until crystallization began (about 1.5 L remaining)To the remaining slurry was added n-hexane (1.5 L, 1.5 volumes) whilemaintaining the temperature of the solution at about 45° C. After theaddition of n-hexanes was complete, cool the solution to 0 to 5° C. overthe period of about 3 hr and agitate the resulting slurry at thistemperature for at least 2 hr before filtration. The crystals were thenfiltered and washed with chilled (<5° C.) ethyl acetate/hexane (1:2)(0.3 L, 0.3 volume). The collected crystals of the title compound werethen dried under a vacuum at a temperature of about 40-45° C. until aconstant weight was observed. The typical yield for this two-step onepot process (reduction and acetylation) is 80-89%.

¹H (500 MHz, CDCl₃) δ 5.18, 4.93, 4.75, 4.74, 4.59, 4.52, 4.13, 1.08,3.74, 3.60, 3.48, 3.43, 2.84, 2.73, 2.72, 2.66, 2.55, 2.43, 2.26, 2.02,1.73, 1.69, 1.46, 1.39, 1.33, 1.31, 1.26, 1.23, 1.23, 1.23, 1.10, 0.97,0.91.

¹³C (125 MHz, CDCl₃) δ 184.9, 178.0, 174.9, 170.1, 142.1, 122.4, 99.8,81.6, 79.1, 78.2, 77.5, 77.3, 77.0, 76.3, 76.2, 73.8, 71.9, 69.1, 65.9,63.4, 43.8, 40.9, 40.0, 38.4, 36.3, 35.7, 31.1, 25.7, 23.3, 21.7, 21.4,20.0, 19.7, 17.2, 16.0, 14.7, 12.0, 7.9.

Example 6 Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Imine Acetamide 2′-Acetate 3-ketolide (Compound of Formula (VII-b))

A solution of NCS (0.789 kg, 5.908 mol, 1.4 eq) in CH₂Cl₂ (water=20 ppm,9 L) was cooled to −15° C. Dimethylsulfide (0.590 L, 8.018 mol, 1.9 eq)was added and the reaction mixture was agitated at −15° C. for 15 to 20min. A solution of the title compound of Example 5 (3.0 kg, 4.220 mol,1.0 eq) in CH₂Cl₂ (6 to 8 L) at −20° C. and the reaction mixture wasagitated at −20° C. for 3 hours. Triethylamine (0.882 L, 6.33 mol, 1.5eq) was added and the reaction mixture was agitated at −15° C. for 1hour. The reaction mixture was warmed up to 5° C. and diluted with EtOAc(18 vols), and then it was washed with aq. sat. NAHCO₃ (4 vols×2) andwith aq. half-sat. NaCl (4 vols). The organic layer was separated andconcentrated under reduced pressure to as low volume as possible.Acetonitrile (4 vols) was added and the solution was concentrated untilabout 2.5 to 3 remaining vols. Slowly cool down to about 5° C. and holdthe slurry at this temperature for 2 hrs. Filter and wash with chilledMeCN (0.1 vol). Vacuum dry at 50° C. for 24 hrs or until constant weightafforded the titled compound 2.13 kg (71.2% yield), 97.2% purity byHPLC. MS-ESI m/z 709.37 (M+H)⁺.

Example 7 Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Imine Propionamide-2-fluoro-2′-Acetate 3-ketolide (Compound of Formula(VIII-c)) Step 7a. Preparation of 3-Decladinose-6,11-O,O-BridgedErythromycin A 9-Imine Acetamide-2-fluoro-2′-Acetate 3-ketolide(Compound of Formula (VIII))

A clear solution of the title compound of Example 6 (1.3 kg, 1.834 mol,1 eq) in N-methylpyrrolidinone (anhydrous, 7.28 L, 5.6 vols) and t-BuOH(1.82 L, 1.4 vols) was cooled to −15° C. t-BuOLi solid (0.184 kg, 2.293mol, 1.25 eq) was added in one portion and the reaction mixture wasagitated for 1 hour. The reaction mixture was cooled to −30° C. and NFSI(0.566 kg, 1.797 mol, 0.98 eq) was added in less than 5 min. Thereaction mixture was agitated for 25 mins and then poured into astirring mixture of EtOAc (11 vols) and half-saturated aq. NaHCO₃ (6vols). The aqueous layer was separated and extracted with EtOAc (3vols). The organic layers were combined, washed with aq. sat. NaHCO₃ (4vols) and with aq. half-sat. NaCl (4 vols), and then dried with Na₂SO₄(1 kg) overnight. The mixture was concentrated to dryness to afford athick oil. Vacuum dry at 40° C. for 24 h afforded a thick light brownsyrup, yield=1.4 kg (105% yield due to residual NMP), HPLC purity=86%.MS-ESI m/z 727.37 (M+H)⁺.

Step 7b. Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Imine-2-fluoro-2′-Acetate 3-ketolide

To a clear solution of the crude product from step 7a (syrup, ˜86%purity by HPLC, 1.4 kg, 1.834 mol maximum) in absolute EtOH (5.6 L) wascharged methanesulfonic acid (0.5 L, 4 eq). The reaction mixture wasagitated at 50° C. for 2 hours and then cooled to 20° C. The reactionmixture was poured in to EtOAc (20 vols), washed subsequently with 10 wt% aq. K₂CO₃ (6 vols). sat. aq. NaHCO₃ (8 vols) and half-sat. aq. NaCl (6vols). The organic solution was dried with Na₂SO₄ (2 kg) overnight andthen concentrated to a very small remaining volume (˜1 vol) at whichpoint the crystallization of the product occurs. The slurry was slowlycooled down to ca. 0° C. and held at this temperature for 1 h. Thecrystals were filtered and washed with EtOAc (0.3 L). Vacuum dry at 30°C. for 24 h afforded a white solid product, purity=97% by HPLC,yield=0.8 kg (64% for 2-fluorination and 9-deacetylation). MS-ESI m/z685.48 (M+H)⁺.

Step 7c. Preparation of 3-Decladinose-6,11-O,O-Bridged Erythromycin A9-Imine Propionamide-2-fluoro-2′-Acetate 3-ketolide (Compound of Formula(VIII))

To a clear solution of the product from step 7b (0.8 kg, 1.168 mol) inCH₂Cl₂ (6 L, 7.5 vols) was charged propionic anhydride (165 ml, 1.285mol, 1.1 eq). The reaction mixture was agitated at 20° C. for 5 hoursand then concentrated to dryness to leave a thick oil. Vacuum dry at 30°C. for 24 hrs afforded an off-white amorphous solid, purity=96% by HPLC,yield=0.89 kg (103% yield due to excess anhydride and propionic acidby-product). MS-ESI m/z 741.67 (M+H)⁺.

Example 8 Preparation of 3-Decladinose-6,11-O,O-Bridged KetoneErythromycin A 9 Imine Propionamide-2-fluoro-2′-Acetate 3-ketolide(Compound of Formula (IXb))

A solution of the titled compound of Example 7 (96% by HPLC, 120 g) inmethylene chloride (200 ml, 1.7 vols) was cooled with dry ice-acetonebath. Methanesulfonic acid (11.6 ml, 1.1 eq) was added followed by MeOH(400 ml, 3.4 vols). O₃ gas from the ozone generator was bubbled into thereaction mixture until a light blue color stayed. Oxygen was bubbled infor about 5 to 10 minutes to blow away excess O₃. Dimethyl sulfide (15.5mL, 1.3 eq.) was added to quench the reaction. The cooling bath wasremoved and the reaction mixture was slowly warmed up to about ˜5 to 0°C. EtOAc (25 vols) was added and the reaction mixture was washedsubsequently with saturated aqueous sodium bicarbonate (10 vols) andhalf-saturated aq. brine (10 vols). The organic layer was concentratedto dryness to leave a stick oil. Absolute EtOH (3 vols) was added andthe solution was concentrated to ca. 0.3 to 0.5 vol. The slurry wasslowly cooled down to ca. 10° C. and held at this temperature for 1 hbefore filtration and washing with EtOH (0.2 vol). Vacuum dry at 30° C.for 12 to 24 h afforded a white solid product, purity=93% by HPLC,yield=˜70 g (60% yield). MS-ESI m/z 743.38 (M+H)⁺.

Example 9 Preparation of Compound of Formula (X-c) Step 9a. Addition ofO-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine (Compoundof Formula (XI))

A solution ofO-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine (Compoundof formula (XI) in EtOH (22 L, 11 vols) was cooled to −35° C. The titledcompound of Example 8 (2.3 Kg) was added. Aqueous HCl (1.5N, 4.44 L,2.15 eq) was added slowly within 1 h (maintain inner temperature<−30°C., reaction mixture pH˜3.5). The reaction mixture was agitated at <−30°C. for 1 h. The cold reaction mixture was poured into a stirring mixtureof EtOAc (38 vols), saturated sodium bicarbonate (13 vols) and water (4vols). The organic layer was separated and the aqueous layer wasextracted with EtOAc (7 vols). The organic layers were combined andwashed with brine (8 vols). The organic solution was concentrated todryness and vacuum dried at 30° C. for 20 h to afford dark brownamorphous solid, purity (E isomer)=˜53% (E/Z=4.1:1), yield=3.438 Kg(117%, contains 13-18% 2′-deacetylated product). MS-ESI m/z 947.47(M+H)⁺, 474.17 (M+2H)²⁺.

Step 9b. 2′-Deprotection

The crude product from step 9a (1.01 Kg, 70.4% purity for 2′-OAc+2′-OH)was dissolved in MeOH (10 L, 10 vols) and agitated at room temperaturefor 19 h. The reaction mixture was concentrated to about 2.5 remainingvolumes (2.5 L) and held at room temperature for 2 h before filtrationand washing with MeOH (0.5 L) Vacuum dry at 25° C. for 20 h afforded ayellow solid, purity=90.9% (E/Z=39:1), yield=0.518 Kg (52%). The crudeproduct was dissolved CH₂Cl₂ (4 vols) and filtered. The filtrate wasconcentrated to about 1.85 vols. MeOH (8.6 vols) was added and themixture was concentrated to about 4-4.5 remaining volumes. The slurrywas held at 15-18° C. for 3 h before filtration and wash with MeOH (0.5L). Vacuum dry at 30° C. for 20 h afforded the title compound,purity=94.5%, recovery yield=86.5%. MS-ESI m/z 905.28 (M+H)⁺, 453.08(M+2H)²⁺.

Example 10 Preparation of 5-bromo-2-chloromethyl-pyridine hydrochloride(Compound of Formula (XI-a))

A mixture of (5-bromo-pyridin-2-yl)-methanol (104 g, 0.66 mol) inmethylene chloride (833 mL) in two neck flask was placed in water bath.Thionyl chloride (80.5 mL, 1.33 mol) was dropwise added to the reactionmixture using dropping funnel and stirred at room temperature for 1.5hr. Then, thionyl chloride (20 mL, 0.33 mol) was additionally added tothe reaction mixture and stirred for 2.5 hr. After completion of thereaction, the reaction mixture was transferred to a round bottom flask.Methylene chloride and thionyl chloride were evaporated off. Toluene(2×100 mL) was added to the residue and azeotropically removed all theresidual thionyl chloride. The residue was dried on vacuum for overnightto give the title compound (129.6 g, 96%) as a pink solid. MS-ESI m/z207.91 (M+H)⁺.

Example 11 Preparation of2-(5-Bromo-pyridin-2-ylmethoxy)-isoindole-1,3-dione (Compound of Formula(XI-b))

To a mixture of 5-Bromo-2-chloromethyl-pyridine hydrochloride (63.7 g,0.262 mol) and N-hydroxylphthalimide (64 g, 0.393 mol) in acetonitrile(400 mL) was placed in water bath and added N,N-diisopropylethylamine(182 mL, 1.05 mol) using dropping funnel for 10 min. It was heated at65° C. for 4 hrs and evaporated off the solvent and extra base. Then,water (100 mL) was added to the reaction mixture and stirred forovernight. The resulting solid was filtered, washed with water (2×50 mL)and acetonitrile (100 mL). The white solid was dried on vacuum pump toprovide the title compound (84.2 g, 84%) as a white solid. MS-ESI m/z334.95 (M+H)⁺.

Example 12 Preparation of2-(5-Trimethylstannyl-pyridin-2-ylmethoxy)-isoindole-1,3-dione (Compoundof Formula (XI-c))

A mixture of 2-(5-bromo-pyridin-2-ylmethoxy)-isoindole-1,3-dione (50 g,0.15 mol), hexamethylditin (54.17 g, 0.165 mol) in toluene (300 mL) wasdegassed (3 times) and filled with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (3.47 g, 3.0 mmol) was added tothe reaction mixture, which was degassed again. The reaction was heatedat 90° C. for 18 hrs. After removal of solvent, the crude product waspurified with silica gel column chromatography using 0-35% ethylacetatein hexane to provide the title compound (47.6 g, 76%) as a pale yellowsolid. MS-ESI m/z 418.96 (M+H)⁺.

Example 13 Preparation of Compound of Formula (XI-d)

A mixture of 2-(2 bromothiazol-4-yl)-isoindole-1.3-dione (927 mg, 3.0mmol), 2-(5-trimethylstannyl-pyridin-2-ylmethoxy)-isoindole-1,3-dione(1.25 g, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (173 mg,0.15 mmol) in toluene (15 mL) was placed in sealed tube, degassed andfilled with nitrogen three times. It was heated at 160° C. for 60 min(×3) in microwave. After being cooled, it was filtered, washed withacetonitrile and dried on vacuum to afford the title compound (1.08 g,74%) as a yellow solid. MS-ESI m/z 483.08 (M+H)⁺.

Example 14 Preparation ofO-[5-(4-Amino-thiazol-2-yl)-pyridin-2-ylmethyl]-hydroxylamine (Compoundof Formula (XI))

To a mixture of the product from Example 13 (400 mg, 0.83 mmol) andmethanol (4 mL) was added 33% methylamine in ethanol (2 mL). It washeated at 60° C. for 45 min. After being cooled, it was filtered andevaporated to give the title compound (>95% pure) as a yellow solid.MS-ESI m/z 223.11 (M+H)⁺.

Example 15 Preparation of (5-trimethylstannyl-pyridin-2-yl)-methanol(Compound of Formula (XI-f))

A mixture of (5-bromo-pyridin-2-yl)-methanol (2.5 g, 13.3 mmol) andhexamethylditin (2.8 mL, 13.3 mmol) in abs. THF (10 mL) was cooled to−78° C. and degassed and filled with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.1995 mmol) was addedto the reaction mixture, which was degassed. The reaction mixture wasallowed to warm to room temperature and heated in microwave at 120° C.for 20 min. After removal of solvent, the crude material was purifiedwith silica gel column chromatography using 30-70% ethylacetate inhexane to provide the title compound (2.91 g, 80%) as a pale yellowsolid. MS-ESI m/z 274.03 (M+H)⁺.

Example 16 Preparation of2-[2-(6-hydroxymethyl-pyridin-3-yl)-thiazol-4-yl]-isoindole-1,3 dione(Compound of Formula (XI-g))

A mixture of 2-(2 bromothiazol-4-yl)-isoindole-1.3-dione (10.0 g, 32.3mmol) and (5-trimethylstannyl-pyridin-2-yl)-methanol (12.2 g, 26.9 mmol)in abs. toluene (50 mL) was placed in sealed tube, degassed and filledwith tetrakis(triphenylphosphine)palladium(0) (932 mg, 0.8 mmol). Thereaction mixture was heated at 160° C. for 1.5 hr and filtered while thereaction mixture was hot. After being cooled to room temperature for 2hr, a solid was filtered through fritted funnel, washed with toluene (30mL) and dried on vacuum to provide the title compound (6.2 g, 75%) as apale yellow solid. MS-ESI m/z 338.02 (M+H)⁺.

Example 17 Preparation of Compound of Formula (XI-d)

A mixture of the product from Example 16 (7.375 g, 21.88 mmol),N-hydroxyphthalimide (4.159 g, 25.52 mmol) and triphenylphosphine (7.46g, 28.45 mmol) in freshly distilled THF (44 mL) was stirred at roomtemperature for 10 min and located in water bath. Then, DIAD (5.6 mL,28.45 mmol) was dropwise added to the reaction mixture for 6 min andstirred for 3 hrs. A solid was filtered through a fritted funnel, washedwith 50% THF in hexane (30 mL) and dried on vacuum pump to give thetitle compound (7.34 g, 70%) as a yellow solid. MS-ESI m/z 483.09(M+H)⁺.

Although the invention has been described in detail with respect tovarious preferred embodiments it is not intended to be limited thereto,but rather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

What is claimed:
 1. A process of preparing a compound of formula (XI):

the process comprising the steps of: (a) halogenating(5-bromo-pyridin-2-yl)-methanol with a chlorinating reagent to produce acompound of formula (XI-a)

(b) reacting the compound of formula (XI-a) with

 in the presence of a base, to produce a compound of formula (XI-b):

 wherein A and B are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or A and Btaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic; (c) reacting thecompound of Formula (XI-b) with a tin reagent in the presence of ametallic catalyst to produce a compound of formula (XI-c):

 where Y is an aliphatic group; (d) reacting the compound of formula(XI-c) with a compound of the formula

 in the presence of a metallic catalyst to produce a compound of formula(XI-d):

 wherein C and D are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or C and Dtaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic and wherein X is aleaving group; and (e) hydrolyzing the compound of formula (XI-d) with abase in a protogenic organic solvent or aqueous solution, therebyproducing the compound of formula (XI).
 2. The process of claim 1,wherein in step (a), the chlorinating agent is thionyl chloride.
 3. Theprocess of claim 1, wherein in step (b), the base isN,N-diisopropylethylamine.
 4. The process of claim 1, wherein in step(c), the tin reagent is hexamethylditin and and the metallic catalyst istetrakis(triphenylphosphine)palladium(0).
 5. The process of claim 1,wherein in step (d), the metallic catalyst istetrakis(triphenylphosphine)palladium(0).
 6. The process of claim 1,wherein in step (e), the base is methylamine.
 7. A process of preparinga compound of formula (XI):

the process comprising the steps of: (a) reacting(5-bromo-pyridin-2-yl)-methanol with a tin reagent in the presence of ametallic catalyst to produce a compound of formula (XI-f):

 where Y is an aliphatic group; (b) reacting the compound of formula(XI-f) with a compound of the formula

 in the presence of a metallic catalyst to produce a compound of formula(XI-g):

 wherein C and D are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or C and Dtaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic and wherein X is aleaving group; (c) reacting the compound of formula (XI-g) with acompound of the formula

in the presence of dehydrating agents to produce a compound of formulae(XI-d):

 wherein A and B are each independently hydrogen, a substituted orunsubstituted aliphatic group, a substituted or unsubstituted cyclicgroup, a substituted or unsubstituted heterocyclic group, a substitutedor unsubstituted aryl group, a substituted or unsubstituted alicyclicgroup, or a substituted or unsubstituted heteroaryl group; or A and Btaken together with the carbon to which they are attached form a cyclicmoiety selected from: aryl, substituted aryl, heterocyclic, substitutedheterocyclic, alicyclic, or substituted alicyclic; and (d) hydrolyzingthe compound of formula (XI-d) with a base in a protogenic organicsolvent or aqueous solution, thereby producing the compound of formula(XI).
 8. The process of claim 7, wherein in step (a), the tin reagent ishexamethylditin and the metallic catalyst istetrakis(triphenylphosphine)palladium(0).
 9. The process of claim 7,wherein in step (b), the metallic catalyst istetrakis(triphenylphosphine)palladium(0).
 10. The process of claim 7,wherein in step (c), the dehydrating agents are triphenylphosphinetogether with diisopropyl azodicarboxylate.
 11. The process of claim 7,wherein in step (d), the base is methylamine.